Presented by Rutendo Kuwana

1. Evaluation of quality and interchangeability of medicinal productsTraining workshop for evaluators from National Medicines Regulatory Authorities in East Africa Community10-14 September 2007, Dar Es Salaam, Tanzania Presented by Rutendo Kuwana Dissolution Testing

2. Dissolution testing: conventional tablets and capsules • It measuresthe portion (%) of the API that (1) has been released from tablets/capsules and (2) has dissolved in the dissolution medium during controlled testing conditions within a defined period • The tablet thus first disintegrates • Then the API will be able to dissolve • Slow disintegration➜ slow dissolution • The % API dissolved is determined with an appropriate validated method: UV/VIS, HPLC, AA, GC, etc • Dissolution testing is also applicable to suspensions and suppositories

3. Solid oral dosage forms Immediate release typically means that 75% of the API is dissolved within 45 minutes • Rapidly dissolving: ≥ 85% in ≤ 30 minutes • Very rapidly dissolving: ≥ 85% in ≤ 15 minutes

4. Challenges in Dissolution Testing Dissolution testing in immediate-release (IR) solid dosage forms poses many challenges • developing and validating the test method • ensuring that the method is discriminatory • addressing the potential for an in vivo–in vitro relationship (IVIVR) or correlation (IVIVC).

5. Why in-vitro dissolution testing?

6. Applications • For selection of the formulation in the development phase • By comparison of the dissolution profiles of innovator product with those of formulations • Hint: start with comparator product to see: • Immediate release? • Rapidly dissolving? • Very rapidly dissolving? • Disintegration testing can aid in the early phases • This should be a basic strategy in R&D to maximize the chances of bioequivalence

7. Applications (cont.) • It is a requirement for comparative dissolution data for the bio-batch and innovator batch • Same batches as used in bioequivalence study • Submit report with data, profile comparison & discussion (see report requirements) • This report forms part of pharmaceutical development report • Inclusion of the same report in the bioequivalence study report is recommended

8. Applications (cont.) • Demonstration of in vivo bioequivalence of one or more of the lower strength(s) of an FPP may be waived based on • an acceptable in vivo BE study of the highest strength against the comparator product • demonstration of similarity of dissolution profiles, • if the lower strength is proportionally similar in formula to the higher strength (bio-batch) and • if all pharmacokinetic requirements are met

9. Applications (cont.) • Comparison of the release properties of pivotal batches • To demonstrate in vitro similarity of such batches • This is considered essential for retention of efficacy and safety • Note that bioequivalence studies are done normally only once on a bio-batch during development • It must be demonstrated that the product retains the dissolution characteristics up to production scale • The studies should be submitted in dossier as part of the FPP development report

10. Applications (cont.) • Selection of the dissolution specifications for product release & stability purposes • Conditions and acceptance criteria to be set • The dissolution profiles of the bio-batch should be used for this purpose • A dissolution specification should be able to detect inadequate release properties of the commercial batches • A “generous” dissolution limit has no quality selectivity

11. Applications (cont.) • Post-approval amendment application • Assessment of formulation changes to demonstrate that the profiles of the amendment batch and the current batch are similar

12. Variables affecting dissolution • characteristics of the API e.g., particle size, crystal form, bulk density • product composition e.g., drug loading, and the identity, type, and levels of excipients • manufacturing process e.g., compression forces, equipment • effects of stability storage conditions e.g., temperature, humidity

13. Mechanism of dissolution Dissolution test determines the cumulative amount of drug that goes into solution as a function of time Steps involved • liberation of the solute or drug from the formulation matrix (disintegration) • dissolution of the drug (solubilization of the drug particles) in the liquid medium The overall rate of dissolution depends on the slower of these two steps

14. Mechanism of dissolution First Step Cohesive properties of the formulated solid dosage form drug play a key role disintegration and erosion semi- solid or liquid formulations, the dispersion of lipids or partitioning of the drug from the lipid phase is the key factor If the first step of dissolution is rate-limiting, then the rate of dissolution is considered to be disintegration controlled

15. Mechanism of dissolution Second Step Solubilization of the drug particles depends on the physicochemical properties of the drug such as its chemical form (e.g., salt, free acid, free base) and physical attributes

16. Dosage form type and design affect dissolution testing (1) For intrinsic dissolution-limited absorption (i.e., the disintegration of the dosage form is rapid, but dissolution is slow) reduce the particle size of the API Small particle size creates challenges as they can pass through filters and subsequently dissolve

17. Dosage form type and design affect dissolution testing (2) For solubility-limited absorption (intrinsic- solubility controlled) enhance the transient solubility of the API • different salt forms of the API • surfactants in the formulation • solubilized liquid formulations in hard or soft gelatin capsules • non-crystalline materials

18. Media selection For batch-to-batch quality testing medium selection may be based on the solubility data and the dose range of the drug product to ensure that sink conditions are met The term sink conditions is defined as the volume of medium at least greater than three times that required to form a saturated solution of a drug substance.

19. Media selection (2) When the dissolution test is used to indicate the biopharmaceutical properties - closely simulate the environment in the GIT than sink conditions First evaluate using test media within the physiologic pH range of 1.2–6.8 (1.2–7.5 for modified-release formulations)

20. Apparatus selection Described in the United States Pharmacopoeia (USP) under the General Chapters of Dissolutionand Drug Release

21. Discriminatory power The discriminatory power of the dissolution method is the method’s ability to detect changes in the drug product. Once a discriminating method is developed, the same method should be used to release product batches for future clinical trials, if possible.

22. Alternative methods to dissolution testing In ICH Q6A permits use of disintegration testing as a surrogate for conventional Compendial dissolution tests, provided • highly soluble drug substances • intrinsic rate of solubilization is rapid • overall drug release rate is dominated by cohesive properties of the formulation

23. Alternative methods to dissolution testing (2) APIs with good solubility at gastric pH levels may be granted BCS Class I and III classification i.e. may be characterized by disintegration testing alone In liquid filled capsule drug dissolved in solubilization aids offering a true mechanism for drug release is likely to be the rupture of the capsule use disintegration as a surrogate for the QC dissolution test

24. Multi-point dissolution? In multipoint dissolution • multiple (≥ 3) samples are withdrawn from the dissolution medium during dissolution testing • at pre-determined time points and • each sample is analysed for the % API dissolved • A graph of % API dissolved against time: • The dissolution profile

25. Multi-point dissolutionExample of dissolution profile

26. Comparative dissolution testingThe principle • Two or more products or batchescontaining the same API are compared • The strength of products / batches may or may not be the same (depending on purpose of test) • The dissolution conditions are similar, e.g. • Apparatus, medium, volume, rotation speed & temp. • Minimize possible experimental differences in conditions • Samples are taken at the same time points and the data (dissolution profiles) compared • Calculations: correct for volume change of dissolution medium

27. Comparative dissolution testingProfile similarity determination Two conditionsto determine if the dissolution profiles of two products/batches in a particular dissolution medium are similar: • If both the test and reference product show more than 85% dissolution within 15 minutes, the profiles are considered to be similar • No calculations are required If this is not the case, apply point 2 • Calculate the f2 value (similarity factor): • If f2 ≥ 50, the profiles are normally regarded similar

28. Comparative dissolution testingSimilarity factor f2 n = number of time points R(t) = mean % API dissolved of reference product at time point x T(t) = mean % API dissolved of test product at time point x • Minimum of 3 time points (zero excluded) • 12 units (each in own dissolution vessel) for each product (for “official” purposes) • Only one measurement should be considered after both products have reached 85 % dissolution • RSD at higher time points ≤ 10%

29. Comparative dissolution testingDissolution conditions (study design)

30. Typical time pointsImmediate release tablets (capsules) Rationale: • Condition 1 • ≥ 85% dissolution of both products within 15 minutes • 15 minute time point thus essential • Condition 2, for calculation of f2 • a minimum of 3 points are required • Only one measurement should be considered after 85 % dissolution (both tablets) • 20 minute time point thus first possible one (if 15 minute fails 1st condition)

31. Comparative dissolution testingComparison of products Dissolution properties of two products (batches) regarded as similar when • The profiles are similar • in all three media • Statements of instability or insolubility are not acceptable, but should be demonstrated / justified

32. Example Determination of similarity of profiles

33. ExampleDetermination of similarity of profiles (cont.)

34. Reporting Comparative dissolution data Full report, including • Purpose of study • Products/batches information • Batch number, manufacturing/expiry date, packaging, etc. • CoA & size for “own” batches (and BMR for bio-studies report) • Dissolution conditions and method • Analytical method or reference to part of dossier • Results (% API dissolved) • Tabulated • Graphically • Similarity determination / calculation • Conclusion

35. Guidelines WHO Prequalification • Supplement 1 [for use from July 2005 (CPH25)] to: Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis Dissolution testing Others • Guidance for Industry. Waiver of In-Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), August 2000. • CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence. The European Agency for the Evaluation of Medicinal Products CPMP/EWP/QWP/1401/98, July 2001 • SADC Guidelines (Draft)

36. Some conclusions • Comparative dissolution • should form an essential part of R&D of solid oral dosage forms (including suspensions), • supports bio-studies, • is required for comparison of pharmaceutical release properties of pivotal batches, • is used to set dissolution specifications, and • assists in post-approval changes • It is thus important • to conduct the studies under controlled conditions in the 3 media, all as required by the guidelines, • to take samples for analysis at meaningful intervals and • to be able to determine similarity of profiles